Most T cells bearing receptors for antigen made up of alpha and beta chains (TCRs) react with foreign antigens in the form of peptides derived from the antigen bound to grooves on major histocompatibility complex proteins (MHC). Immunologists have long wondered why T cells are so fixated on MHC. Developing thymocytes must pass 2 tests before they are allowed to develop into mature T cells. They are positively selected, via the reaction of their TCRs with MHC + self peptide. However they are negatively selected and die if their TCRs react too well with MHC. It is thought that positive selection explains the obsession of TCRs for MHC. However, it has also been suggested that TCRs might have been selected evolutionary to have some underlying specificity for MHC. Recent data suggest that the TCRs which would demonstrate the evolutionary idea most clearly are missing from mature T cells because thymocytes bearing these TCRs are negatively selected in the thymus. This proposal will test whether this is indeed so. Also to be studied are a collection of TCRs which obey the predictions of an evolutionary hypothesis. These TCRs crossreact with many alleles of MHC and both classes of MHC, thus they appear to be reacting with some feature of MHC which is common to all such molecules. Experiments will investigate whether the common element(s) are conserved side chains of the MHC proteins. Additionally, the importance of the backbone shape of MHC proteins will be investigated, with studies on TCR interactions with an MHC protein, CD1d, which has a geometry which differs from that of classical MHC proteins. The fact that TCRs react with MHC bound to antigens has to be taken into account in the design of vaccines and in knowledge of autoimmunity. However the rules which govern TCR interaction with MHC are not well understood. Moreover, it is possible that T cells bearing the crossreactive TCRs that are the subject of this proposal contribute directly to autoimmune disease. These studies will therefore illuminate several crucial subjects in T cell biology.